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TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study
Wo-Tu Tian1,2, Fei-Xia Zhan1,2,3, Zhen-Hua Liu2,4
1Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Background:
Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations.
Objective:
We aimed to explore the potential causative gene for PKD.
Methods:
A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing.
Results:
Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups.
Conclusions:
We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.
Insights
Researchers identified Transmembrane Protein 151A (TMEM151A) as a new gene linked to paroxysmal kinesigenic dyskinesia (PKD). This discovery expands the genetic understanding of PKD, particularly in sporadic cases with pure phenotypes.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Paroxysmal kinesigenic dyskinesia (PKD) is a common movement disorder.
- Only one-third of PKD cases are linked to proline-rich transmembrane protein 2 (PRRT2) mutations, indicating other genetic factors are involved.
Purpose of the Study:
- To investigate the genetic basis of PKD in patients without PRRT2 mutations.
- To identify novel genes associated with the development of paroxysmal kinesigenic dyskinesia.
Main Methods:
- Whole-exome sequencing (WES) was performed on 196 PRRT2-negative PKD probands.
- Case-control analysis using Gene Ranking, Identification and Prediction Tool identified candidate genes.
- Sanger sequencing screened an additional 325 PRRT2-negative PKD probands.
Main Results:
- Transmembrane Protein 151A (TMEM151A) variants were significantly more frequent in PKD patients than controls.
- Twenty-four heterozygous TMEM151A variants were found in 4.80% of probands, including missense and nonsense mutations.
- TMEM151A-related PKD cases often presented as sporadic with a pure phenotype and later onset compared to PRRT2-related cases.
Conclusions:
- Mutations in TMEM151A are associated with paroxysmal kinesigenic dyskinesia, expanding the known genetic spectrum of the disorder.
- TMEM151A-related PKD is more prevalent in sporadic cases and characterized by a pure phenotype and later age of onset.
- Further functional studies are required to elucidate the pathogenic mechanisms of TMEM151A in PKD.
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